Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells

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Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. / Withers, David R.; Hepworth, Matthew R.; Wang, Xinxin; Mackley, Emma C.; Halford, Emily E.; Dutton, Emma E.; Marriott, Clare L.; Brucklacher-Waldert, Verena; Veldhoen, Marc; Kelsen, Judith; Baldassano, Robert N.; Sonnenberg, Gregory F.

In: Nature Medicine, Vol. 22, No. 3, 03.2016, p. 319-323.

Research output: Contribution to journalArticle

Harvard

Withers, DR, Hepworth, MR, Wang, X, Mackley, EC, Halford, EE, Dutton, EE, Marriott, CL, Brucklacher-Waldert, V, Veldhoen, M, Kelsen, J, Baldassano, RN & Sonnenberg, GF 2016, 'Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells', Nature Medicine, vol. 22, no. 3, pp. 319-323. https://doi.org/10.1038/nm.4046

APA

Withers, D. R., Hepworth, M. R., Wang, X., Mackley, E. C., Halford, E. E., Dutton, E. E., Marriott, C. L., Brucklacher-Waldert, V., Veldhoen, M., Kelsen, J., Baldassano, R. N., & Sonnenberg, G. F. (2016). Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. Nature Medicine, 22(3), 319-323. https://doi.org/10.1038/nm.4046

Vancouver

Author

Withers, David R. ; Hepworth, Matthew R. ; Wang, Xinxin ; Mackley, Emma C. ; Halford, Emily E. ; Dutton, Emma E. ; Marriott, Clare L. ; Brucklacher-Waldert, Verena ; Veldhoen, Marc ; Kelsen, Judith ; Baldassano, Robert N. ; Sonnenberg, Gregory F. / Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. In: Nature Medicine. 2016 ; Vol. 22, No. 3. pp. 319-323.

Bibtex

@article{182a0a2f70d6418f9fa619af94aaa912,
title = "Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells",
abstract = "RAR-related orphan receptor-γt (ROR-γt) directs differentiation of proinflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases. However, ROR-γt-dependent group 3 innate lymphoid cells ILC3s provide essential immunity and tissue protection in the intestine, suggesting that targeting ROR-γt could also result in impaired host defense after infection or enhanced tissue damage. Here, we demonstrate that transient chemical inhibition of ROR-γt in mice selectively reduces cytokine production from TH17 but not ILCs in the context of intestinal infection with Citrobacter rodentium, resulting in preserved innate immunity. Temporal deletion of Rorc (encoding ROR-γt) in mature ILCs also did not impair cytokine response in the steady state or during infection. Finally, pharmacologic inhibition of ROR-γt provided therapeutic benefit in mouse models of intestinal inflammation and reduced the frequency of TH17 cells but not ILCs isolated from primary intestinal samples of individuals with inflammatory bowel disease (IBD). Collectively, these results reveal differential requirements for ROR-γt in the maintenance of TH17 cell and ILC3 responses and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation.",
keywords = "Chronic inflammation, Innate lymphoid cells, Translational research",
author = "Withers, {David R.} and Hepworth, {Matthew R.} and Xinxin Wang and Mackley, {Emma C.} and Halford, {Emily E.} and Dutton, {Emma E.} and Marriott, {Clare L.} and Verena Brucklacher-Waldert and Marc Veldhoen and Judith Kelsen and Baldassano, {Robert N.} and Sonnenberg, {Gregory F.}",
year = "2016",
month = mar
doi = "10.1038/nm.4046",
language = "English",
volume = "22",
pages = "319--323",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "3",

}

RIS

TY - JOUR

T1 - Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells

AU - Withers, David R.

AU - Hepworth, Matthew R.

AU - Wang, Xinxin

AU - Mackley, Emma C.

AU - Halford, Emily E.

AU - Dutton, Emma E.

AU - Marriott, Clare L.

AU - Brucklacher-Waldert, Verena

AU - Veldhoen, Marc

AU - Kelsen, Judith

AU - Baldassano, Robert N.

AU - Sonnenberg, Gregory F.

PY - 2016/3

Y1 - 2016/3

N2 - RAR-related orphan receptor-γt (ROR-γt) directs differentiation of proinflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases. However, ROR-γt-dependent group 3 innate lymphoid cells ILC3s provide essential immunity and tissue protection in the intestine, suggesting that targeting ROR-γt could also result in impaired host defense after infection or enhanced tissue damage. Here, we demonstrate that transient chemical inhibition of ROR-γt in mice selectively reduces cytokine production from TH17 but not ILCs in the context of intestinal infection with Citrobacter rodentium, resulting in preserved innate immunity. Temporal deletion of Rorc (encoding ROR-γt) in mature ILCs also did not impair cytokine response in the steady state or during infection. Finally, pharmacologic inhibition of ROR-γt provided therapeutic benefit in mouse models of intestinal inflammation and reduced the frequency of TH17 cells but not ILCs isolated from primary intestinal samples of individuals with inflammatory bowel disease (IBD). Collectively, these results reveal differential requirements for ROR-γt in the maintenance of TH17 cell and ILC3 responses and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation.

AB - RAR-related orphan receptor-γt (ROR-γt) directs differentiation of proinflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases. However, ROR-γt-dependent group 3 innate lymphoid cells ILC3s provide essential immunity and tissue protection in the intestine, suggesting that targeting ROR-γt could also result in impaired host defense after infection or enhanced tissue damage. Here, we demonstrate that transient chemical inhibition of ROR-γt in mice selectively reduces cytokine production from TH17 but not ILCs in the context of intestinal infection with Citrobacter rodentium, resulting in preserved innate immunity. Temporal deletion of Rorc (encoding ROR-γt) in mature ILCs also did not impair cytokine response in the steady state or during infection. Finally, pharmacologic inhibition of ROR-γt provided therapeutic benefit in mouse models of intestinal inflammation and reduced the frequency of TH17 cells but not ILCs isolated from primary intestinal samples of individuals with inflammatory bowel disease (IBD). Collectively, these results reveal differential requirements for ROR-γt in the maintenance of TH17 cell and ILC3 responses and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation.

KW - Chronic inflammation

KW - Innate lymphoid cells

KW - Translational research

U2 - 10.1038/nm.4046

DO - 10.1038/nm.4046

M3 - Article

C2 - 26878233

VL - 22

SP - 319

EP - 323

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 3

ER -